rs773670891

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_020451.3(SELENON):c.402_403+2delGAGT(p.Arg135fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 274,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L134L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

SELENON
NM_020451.3 frameshift, splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 0.598

Variant links:

Genes affected

SELENON (HGNC:15999): (selenoprotein N) This gene encodes a glycoprotein that is localized in the endoplasmic reticulum. It plays an important role in cell protection against oxidative stress, and in the regulation of redox-related calcium homeostasis. Mutations in this gene are associated with early onset muscle disorders, referred to as SEPN1-related myopathy. SEPN1-related myopathy consists of 4 autosomal recessive disorders, originally thought to be separate entities: rigid spine muscular dystrophy (RSMD1), the classical form of multiminicore disease, desmin related myopathy with Mallory-body like inclusions, and congenital fiber-type disproportion (CFTD). This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec). Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. A second stop-codon redefinition element (SRE) adjacent to the UGA codon has been identified in this gene (PMID:15791204). SRE is a phylogenetically conserved stem-loop structure that stimulates readthrough at the UGA codon, and augments the Sec insertion efficiency by SECIS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2016]

SELENON links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-25802114-CTGAG-C is Pathogenic according to our data. Variant chr1-25802114-CTGAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461633.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=4}. Variant chr1-25802114-CTGAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3 link	c.402_403+2delGAGT	p.Arg135fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 3 of 13	ENST00000361547.7	NP_065184.2	Q9NZV5-1
SELENON	NM_206926.2 link	c.301+956_301+959delGAGT		intron_variant	Intron 2 of 11		NP_996809.1	Q9NZV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SELENON	ENST00000361547.7 link	c.401_403+1delTGAG	p.Leu134del	splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 3 of 13	1	NM_020451.3	ENSP00000355141.2	Q9NZV5-1
SELENON	ENST00000374315.1 link	c.301+955_301+958delTGAG		intron_variant	Intron 2 of 11	5		ENSP00000363434.1	Q9NZV5-2
SELENON	ENST00000354177.9 link	c.301+955_301+958delTGAG		intron_variant	Intron 2 of 11	5		ENSP00000346109.5	H9KV50
SELENON	ENST00000494537.2 link	n.301+955_301+958delTGAG		intron_variant	Intron 2 of 12	3		ENSP00000508308.1	A0A804HLD6

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000991

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

35924

Hom.:

AF XY:

0.0000501

AC XY:

AN XY:

19970

show subpopulations

Gnomad AFR exome

AF:

0.00264

Gnomad AMR exome

AF:

0.000137

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000655

AC:

AN:

122162

Hom.:

AF XY:

0.0000282

AC XY:

AN XY:

70868

show subpopulations

Gnomad4 AFR exome

AF:

0.00126

Gnomad4 AMR exome

AF:

0.000104

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000467

Gnomad4 OTH exome

AF:

0.000173

GnomAD4 genome

AF:

0.000302

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000988

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000348

Hom.:

Bravo

AF:

0.000366

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy

Pathogenic:3Uncertain:1

Jan 24, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The c.402_403+2del variant in SELENON has not been previously reported in the literature in individuals with SELENON-RM but has been identified in 0.1% (13/9840) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs773670891). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 461633) and has been interpreted as likely pathogenic by Invitae, GeneDx, and PerkinElmer Genomics. Conservation and expression data indicate that this exon might not be biologically relevant for this disease, and therefore this variant is not expected to result in loss of function of SELENON. In summary, the clinical significance of the c.402_403+2del variant is uncertain. ACMG/AMP Criteria applied: none (Richards 2015). -

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the deletion of part of exon 3 (c.402_403+2del) of the SELENON gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436). This variant is present in population databases (rs773670891, gnomAD 0.1%). This variant has been observed in individual(s) with clinical features of SELENON-related conditions (PMID: 31847883). ClinVar contains an entry for this variant (Variation ID: 461633). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 31, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SELENON c.402_403+2delGAGT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of SELENON function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 274290 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SELENON causing Eichsfeld Type Congenital Muscular Dystrophy (0.0002 vs 0.0011), allowing no conclusion about variant significance. c.402_403+2delGAGT has been reported in the literature in the heterozygous state in a sudden death of a young individual (Salfati_2019). This report does not provide unequivocal conclusions about association of the variant with Eichsfeld Type Congenital Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 461633). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Mar 12, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Deletions involving coding exons of this gene are a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21131290, 21670436) -

Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion

Pathogenic:1

Nov 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.41

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over